Psychiatric Annals

CME Article 

Determining Patient Candidacy for Antidepressant Use in Bipolar Disorder

Joseph F. Goldberg, MD

Abstract

The psychiatric literature is filled with strong sentiments condemning antidepressant use as inappropriate or otherwise harmful to treatment outcomes in bipolar disorder. However, the literature from prospective controlled trials actually shows that monoaminergic antidepressants are neither all-good nor all-bad, but rather, like most medications, can be beneficial, detrimental, or ineffective according to individual patient subtypes and profiles. Large randomized trials point to lack of efficacy, more than risk for polarity switch or cycle acceleration, as the overriding concern when using antidepressants for bipolar disorder. Underappreciated is that the extant literature is based on only a small handful of antidepressants, with a striking lack of randomized trials using any antidepressants developed after 1999, limiting the extent to which class generalizations can be drawn fairly. Clinicians are encouraged to think of individualized bipolar patient candidacy for antidepressant use in light of identifiable patient-specific moderators of treatment outcome. [Psychiatr Ann. 2019;49(9):386–391.]

Abstract

The psychiatric literature is filled with strong sentiments condemning antidepressant use as inappropriate or otherwise harmful to treatment outcomes in bipolar disorder. However, the literature from prospective controlled trials actually shows that monoaminergic antidepressants are neither all-good nor all-bad, but rather, like most medications, can be beneficial, detrimental, or ineffective according to individual patient subtypes and profiles. Large randomized trials point to lack of efficacy, more than risk for polarity switch or cycle acceleration, as the overriding concern when using antidepressants for bipolar disorder. Underappreciated is that the extant literature is based on only a small handful of antidepressants, with a striking lack of randomized trials using any antidepressants developed after 1999, limiting the extent to which class generalizations can be drawn fairly. Clinicians are encouraged to think of individualized bipolar patient candidacy for antidepressant use in light of identifiable patient-specific moderators of treatment outcome. [Psychiatr Ann. 2019;49(9):386–391.]

The use of antidepressants to treat depressive phases or components of bipolar disorder can neither be condemned nor endorsed without carefully evaluating individual clinical cases and circumstances… No simple guidelines can be provided.1

Few topics in psychopharmacology evoke such vigorous debate as the use of antidepressants in patients with bipolar disorder. The passion with which some authors disparage antidepressant use is matched perhaps only by the astonishing paucity of research on their safety and efficacy for this condition. That trend shows little end in sight as many clinicians and other stakeholders accept as a foregone conclusion the proposition that antidepressants for bipolar disorder are broadly ineffective, hazardous to mood stability, or both. The International Society for Bipolar Disorders (ISBD) Task Force on Antidepressant Use in Bipolar Disorder1 acknowledges that “the available evidence concerning both the value and the risks of antidepressant treatment in bipolar disorder is remarkably limited, and much of it is methodologically weak. Therefore, it is not currently possible to make firm clinical recommendations that are soundly evidence based.” Yet, research on antidepressant safety and efficacy has nearly ground to a halt, as if the existing database is less scant and more definitively negative than the ISBD Task Force thinks.

Risk of Antidepressant-Associated (Hypo)mania

When asked what particular “issues” surround the use of antidepressants in bipolar disorder, many clinicians cite concerns about mania induction or cycle acceleration. However, the literature suggests that distinct affective polarity switches unequivocally triggered by antidepressants are rare. In the largest meta-analysis of this issue to date (comprised of 51 studies with 10,098 participants), the pooled occurrence rate of treatment-emergent mania/hypomania was 18.8%, with a higher incidence among retrospective (30.9%) than prospective (14.4%) or randomized (11.8%) studies.2 But, such risk ratios do not address event risk relative to the spontaneous base rate of post-depressive manias/hypomanias in matched bipolar patients not exposed to antidepressants. An earlier meta-analysis3 comparing prospectively observed switch rates with antidepressants (event rate = 7.7%) versus placebo (event rate = 7.2%) revealed a number-needed-to-harm of 2,003—indicating that for most bipolar patients, antidepressant-associated polarity switches are uncommon.

In retrospective or cross-sectional studies of mania during antidepressant therapy, causal directions are hard to infer if treatment is nonrandomized, and if confounding factors that predispose some patients to polarity switches are not accounted for. The National Institute of Mental Health's Systematic Treatment Enhancement Program for Bipolar Disorder acute bipolar depression randomized trial,4 which found no differences either in efficacy (∼25%) or switch rates (∼10%) during mood stabilizer therapy alone or with an antidepressant, observed that much of what clinicians infer as iatrogenic polarity switches may simply be the natural course of illness. Additional methodological issues to consider when interpreting this literature include the following:

  • Suspected “switch” events are often identified retrospectively without formal documentation or operational criteria, potentially missing both false-positive and negative events, misattributing subthreshold symptoms as true episodes, and potentially conflating hypomania with other phenomena such as anxious distress or simple agitation or edginess, akathisia, or substance intoxication or withdrawal states.
  • The timeframe for judging likely causal associations between antidepressant exposure and polarity switch is often ignored. The ISBD has proposed counting polarity switches within 8 weeks of antidepressant initiation or dosage increases as “definite,” and those occurring by 12 weeks as “likely,” and those by 16 weeks as “possible.”5 Beyond that timeframe, plausible causality becomes indistinguishable from the natural course of illness.
  • It is often assumed that concomitant use of an antimanic mood stabilizer or antipsychotic medication is a necessary prerequisite to antidepressant treatment in bipolar disorder, mainly for presumed protection against induction of mania or hypomania. In fact, no randomized controlled trial (RCT) has ever demonstrated this to be true. A meta-analysis of 35 trials found no evidence that mood stabilizer cotherapy reduces the likelihood of switch events during antidepressant therapy (15.9% risk during antidepressant plus mood stabilizer, 13.8% risk during antidepressant without mood stabilizer).6

Psychopharmacologists often cite lack of efficacy, more than the potential to induce mania, as the greater concern using antidepressants in bipolar disorder, noting that, with the exception of fluoxetine added to olanzapine or lithium, no RCT in bipolar depression has ever shown greater efficacy with an antidepressant plus mood stabilizer versus a mood stabilizer alone. Sidor and MacQueen3 identified a disappointing number-needed-to-treat of 29 when using antidepressants for bipolar depression. Although such observations have spurred interest in various novel molecules other than monoaminergic drugs, they have also effectively halted studies of newer monoaminergic agents that affect novel serotonin receptors or catecholaminergic receptor target combinations.

The field has all but ceased to pursue randomized placebo-controlled trials of any monoaminergic antidepressants developed after 1999 (including escitalopram, desvenlafaxine, duloxetine, levomilnacipran, transdermal selegiline, vortioxetine, and vilazodone) and a handful of those from the mid-1990s (eg, mirtazapine, citalopram, fluvoxamine) or earlier (eg, nortriptyline, phenelzine, isocarboxazid) for which no controlled data exist in bipolar depression. An April 2019 search of the www.clinicaltrials.gov database using the terms “antidepressant” and “bipolar disorder” for active and/or enrolling RCTs returned 42 responses, only two of which involved a previously unstudied monoaminergic antidepressant (vortioxetine [ ClinicalTrials.gov identifier NCT03598868]; and escitalopram [ ClinicalTrials.gov identifier NCT00958633]).

Are more studies with newer monoaminergic antidepressants needed in bipolar depression, or is there already sufficient evidence? Table 1 summarizes existing RCTs.

Evidence Base of Specific Antidepressant Randomized Controlled Trials in Bipolar Disorder

Table 1:

Evidence Base of Specific Antidepressant Randomized Controlled Trials in Bipolar Disorder

Enrichment: Friend or Foe?

“Enrichment” means selecting patients based on certain baseline characteristics that increase their chances for responding to a given treatment. It is a double-edged sword that trades off generalizability (results do not apply to all-comers) for “cherry-picking” patients most likely to benefit from a particular intervention. In bipoloar II depression, several relapse prevention studies using antidepressant monotherapies have shown significantly better outcomes for selective serotonin reuptake inhibitors (SSRIs) (sertraline, fluoxetine) or venlafaxine than placebo with the important proviso that initial response is robust, as summarized in Table 1. Notably, Altshuler et al.19 found that initial full responders to venlafaxine, sertraline, or bupropion were 6 times more likely than partial responders to remain depression-free or mania-free when continuing antidepressants for 1 year. However, full acute response rates during open-label initial treatment were modest (35% after a first antidepressant trial, 13% with a second, and 9% with third attempt), at a rate of decrement not much different than reported in iterative pharmacotherapy trials of major depressive disorder.

Magnitude of initial acute improvement with an antidepressant appears to heavily influence future course during continued antidepressant therapy. Said differently, partial or incomplete remitters to an acute antidepressant trial are unlikely to improve further with more protracted duration of antidepressant use,19 in contrast to chronic or persistent unipolar depression, where lengthier antidepressant trials often convert partial response to full remissions.

Antidepressant Subtypes

Tricyclic antidepressants20 and venlafaxine16 have been suggested to pose higher inherent risks than SSRIs or bupropion for polarity switch, with speculation that potent noradrenergic effects may be riskier than mainly serotonergic effects, although the putative catecholaminergic effects of bupropion (as well as norquetiapine) seemingly challenge that general hypothesis (Figure 1).

A decision tree for antidepressant use in bipolar disorder.

Figure 1.

A decision tree for antidepressant use in bipolar disorder.

A number of patient-specific characteristics bear on antidepressant candidacy in bipolar disorder (Figure 1). These are elaborated in the following text.

Personal History

Evidence-based medicine includes historical outcomes for an individual patient in tailoring their treatment, meaning that a past personal history of antidepressant response carries inarguable weight (antidepressant candidacy is already established). Similarly, a personal history of poor response or polarity switch with antidepressants diminishes candidacy.

Bipolar Subtypes: I Versus II

Antidepressants appear substantially less likely to induce polarity switches in bipolar II than bipolar I depression.21 In fact, evidence for antidepressant efficacy is far better established in bipolar II than bipolar I depression, making sertraline,15 fluoxetine,8 and venlafaxine17,18 monotherapies among the best-studied pharmacotherapies for bipolar II depression (Table 1). Quetiapine holds the largest monotherapy RCT database for bipolar II depression, where post-hoc analyses from US Food and Drug Administration registration trials comparing 300 mg per day (n = 283), 600 mg per day (n = 289), or placebo (n = 204) yielded medium effect sizes at either dose.22 Cautionary admonitions against using antidepressants without concomitant mood stabilizers pertain to bipolar I depression, because in bipolar II depression RCTs, adjunctive lithium lessens antidepressant efficacy and increases study dropout compared to SSRI monotherapy.15

Mixed Features

The presence of even low-grade mania symptoms during bipolar depressive episodes has been associated with an increased risk for worsening of mania symptoms during antidepressant exposure.23 The Diagnostic and Statistical Manual of Mental Disorders, fifth edition's24 broadened criteria for the “mixed features” specifier encourages clinicians to carefully distinguish pure from “mixed” depressive episodes, with implications for the appropriateness or inappropriateness of antidepressants.

Rapid Cycling

Randomized data indicate that in patients with past-year rapid cycling, the continued use of adjunctive antidepressants after an initial response triples the likelihood of subsequent depressive relapse.25 In a previously mentioned favorable bipolar II depression relapse prevention trial of fluoxetine, lithium, or placebo,8 exploratory analyses of the small rapid cycling subgroup (n = 25) found no better efficacy than placebo with either drug.26 By contrast, secondary analyses of rapid cycling subgroups27 from an earlier bipolar II depression RCT17 revealed better acute antidepressant responses with venlafaxine monotherapy (n = 12) than lithium (n= 15).

Substance Use Comorbidity

Psychoactive substance misuse may correlate with antidepressant-associated mania. Altshuler et al.15 found a significantly higher risk for switch events in bipolar patients with prior drug abuse or dependence (particularly psychostimulants) after controlling for covariates. Elsewhere, retrospective studies have linked histories of substance misuse with 5- to 7-fold increased risks for antidepressant-associated mania or hypomania.28,29

Multiple Antidepressant Trials

Numerous antidepressant trials have been associated with poorer antidepressant response in bipolar disorder,30 analogous to findings in the unipolar depression literature.

Antidepressants for Purposes Other Than Depression in Bipolar Disorder

There is remarkably scant literature on the use of SSRIs or serotonin-norepinephrine reuptake inhibitors specifically to treat comorbid anxiety disorders in bipolar patients. In an FDA registration trial of quetiapine for bipolar depression, paroxetine (as an active comparator) failed to improve depressive symptoms but on a secondary analysis did improve concomitant anxiety symptoms better than placebo.13 Possible anxiolytic, anti-obsessional, or other psychotropic effects of SSRIs in bipolar disorder are largely unstudied.

Conclusion

Antidepressants may be safe and effective for an identifiable minority of bipolar patients with depression, although most are understudied. Relative to other treatment options, baseline characteristics and subdiagnostic features can help guide individualized candidacy in ways most consistent with evidence-based parameters.

References

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Evidence Base of Specific Antidepressant Randomized Controlled Trials in Bipolar Disorder

Antidepressant Main Findings from Meta-Analyses or Individual RCTs
Bupropion Three pooled trials (n= 205) comparing bupropion to other antidepressants: no significant differences in response but lower switch rate (relative risk = 0.34) than with desipramine or venlafaxine (reviewed by Sidor and MacQueen3)
Desipramine Comparable desipramine response (5/10) to bupropion (5/9) but higher switch rates (5/10 vs 1/9, respectively); note very small sample sizes7
Fluoxetine From an enriched sample of patients with acute bipolar depression that responded to fluoxetine, patients randomized to fluoxetine (n= 28) vs lithium (n= 26) vs placebo (n= 27) and treated for 1 year, the hazard of relapse was 2.5 times greater with lithium than fluoxetine, with no differences in hypomanic switches8 6-week acute RCT: adjunctive fluoxetine (n= 30, response: 86%) > placebo (n= 29, response: 38%) or adjunctive imipramine (n = 36, response: 57%); concomitant lithium data unavailable9
Imipramine 6-week acute RCT: imipramine (n= 30, response: 57%) < fluoxetine after 6 weeks (n= 30), same as placebo (n= 29, response:38%); no reported switches9 Similar depression relapse rates but higher mania relapse rates over 30 months with imipramine alone (n= 36) (53%) than lithium alone (n= 42) (26%), or lithium plus imipramine (n= 36) (28%)10 10-week acute RCT: imipramine (n= 39; response: 39%) no different from placebo (n= 43; response: 35%) except when lithium levels subtherapeutic (post-hoc analysis)11 6-week acute RCT (vs tranylcypromine [n= 28]): imipramine (n= 28; response: 48%; 24% switch [lithium cotherapy parameters not specified])12
Paroxetine 10-week acute RCT: paroxetine (n= 35; response: 46%) no different from placebo (n= 43; response: 35%), except when subtherapeutic serum lithium levels (post-hoc analysis)11 8-week RCT: mean change in depression severity with paroxetine (n = 122) no different from placebo (n= 126)13 Significant, comparable improvement either with lithium plus divalproex (n = 16) or either mood stabilizer plus paroxetine (n = 11); less early dropout with paroxetine14
Sertraline 16-week RCT of bipolar II sertraline monotherapy (n= 45): 73% response, 17% switch; poorer when combined with lithium (n= 46): 48% response, 10% switch15 10-week RCT (vs other antidepressants) added to mood stabilizer; sertraline (n= 76) response: 55%, switch: 11.8% (no placebo)16
Tranylcypromine 6-week RCT (vs imipramine [n= 28]); tranylcypromine (n = 28): 81% acute response, 12% switch (lithium co-therapy parameters not specified)12
Venlafaxine 10-week RCT (vs other antidepressants) added to mood stabilizer; venlafaxine (n= 86) response: 43%; switch: 5.8% (no placebo)16 Bipolar II monotherapy: 12-week open RCT: venlafaxine (n= 43; response: 58%) > lithium (n= 40; response: 20%), no significant change in mania symptom scores; higher dropout with lithium than venlafaxine17 Bipolar II monotherapy: 12-week RCT: venlafaxine (n= 65, response: 68%) > lithium (n= 64, response: 34%); no increased risk for polarity switch though no placebo comparison arm18
Authors

Joseph F. Goldberg, MD, is a Clinical Professor of Psychiatry, Department of Psychiatry, Icahn School of Medicine at Mount Sinai.

Disclosure: Joseph F. Goldberg discloses royalties from American Psychiatric Association Publishing; speaking fees from Allergan, Neurocrine, Otsuka, Sunovion, and Takeda-Lundbeck; and consulting fees from Lundbeck, Neurocrine, and Sunovion.

Address correspondence to Joseph F. Goldberg, MD, 128 East Avenue, Norwalk, CT 06851; email: joseph.goldberg@mssm.edu.

10.3928/00485713-20190807-03

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